PROJECT ABSTRACT Background: Evidence points to the importance of early intervention in psychotic disorders to alter illness trajectory and disability. As cognitive deficits and poor functioning are not adequately targeted with current treatment, there is an urgent need to investigate underlying mechanisms of these deficits in early psychosis and risk for psychosis. This K23 application proposes a career development program that incorporates rigorous training with an innovative research agenda aimed at identifying early intervention targets for cognitive deficits in early psychotic illness. Candidate: I am an Instructor in Psychiatry at Harvard Medical School and a psychiatrist specialized in the care of patients with first episode psychosis in the OnTrack Program at McLean Hospital. I am a graduate of the Massachusetts General Hospital/McLean Psychiatry Residency and completed the NIMH T32 Clinical Research Training Program at Harvard Medical School. I have a clinical research background in first episode psychosis and high risk for psychosis. This K23 award will provide me with the support necessary to become an expert in patient-oriented research in psychotic disorders and develop an independent clinical research career. Research: Preliminary evidence shows that energy metabolism is dysfunctional in individuals with first episode psychosis and those at high risk for psychosis. As the human brain is highly metabolically active, metabolic abnormalities may play a key role in the emergence of neuronal dysfunction in psychotic disorders. The proposed research will use 31P magnetic resonance spectroscopy (MRS), functional magnetic resonance imaging (fMRI) and metabolic measures to determine the impact of bioenergetic and insulin abnormalities on cognitive function in patients with first episode psychosis and their unaffected siblings over the course of one-year follow-up. Career development and future program of research: I am proposing to acquire training in the areas of: 1) Cognitive neuroscience, including fMRI; 2) Metabolic signaling in the brain; and 3) Statistical methods for longitudinal data analysis. These goals will be accomplished by formal coursework and mentorship by an exceptionally-qualified team of scientists who are internationally-recognized leaders in research directly relevant to the proposal. Completion of the proposed research and training aims will enable the design of a large-scale longitudinal R01 study aimed at modulating energy metabolism to improve cognition and functioning in early psychosis, while mapping casual pathways using multimodal imaging and metabolic methodology. This K23 proposal will provide the training needed for my development as an independent investigator focused on identifying early intervention targets for cognitive deficits across trajectories of risk and early psychosis. It will provide the foundation for a program of research facilitating the development of personalized clinical interventions to alter the course of early psychotic illness, and ultimately, illness prevention and risk reduction.